Lactoferrin, a protein found in human and cows milk, does not appear to protect premature infants from late-onset infections. When given to babies born before 32 weeks, their risk of acquiring infections, such as sepsis, was virtually the same as those in the control group, about 30%.
Late-onset infections, those occurring 72 hours or more after birth, are a significant cause of illness and even death in newborns. Premature babies are particularly vulnerable. This very large UK based NIHR funded study looked at whether this risk could be lessened by bolstering their immune system with lactoferrin.
A recent Cochrane review had shown that while much of the existing evidence found lactoferrin to be of benefit, it was of poor quality and could not be relied upon. Indeed, findings from this study strengthen the case against it as it seems to make little difference to neonatal outcomes.
Why was this study needed?
Premature babies are vulnerable to infection due to their underdeveloped immune systems and the invasive procedures they have to undergo. It is estimated that 20 to 30% will acquire an infection during their first few weeks of life.
Such babies often can’t feed normally so need artificial feeding. This may be intravenous or by a tube into their stomach, known as enteral feeding. They then miss out on some of the health benefits of natural milk, which has many antimicrobial properties.
Previous studies have suggested that adding lactoferrin to enteral feeds may reduce infections, but the numbers of babies have been too small to provide a definitive result. This large trial helps address the knowledge gap.
What did this study do?
The Enteral Lactoferrin in Neonates (ELFIN) randomised controlled trial involved 37 UK sites and a total of 2,203 babies enrolled less than 72 hours after birth.
The intervention group received lactoferrin, obtained from cow’s milk in powder form. When mixed with water and either breast or formula milk the liquid looked similar to the control group’s mixture (which had sucrose added instead). The dose of lactoferrin was 150mg/kg body weight per day, up to a maximum of 300mg/day. The dose was administered once a day and this continued until 34 weeks gestation.
This large, multi-centre trial was of high quality, with 98% of the infants completing their allocated intervention, thus providing robust evidence.
What did it find?
- No difference was found between groups for the primary outcome of microbiologically or clinically suspected late-onset bloodstream infection. It occurred in 316/1,093 (29%) of the lactoferrin group compared with 334/1,089 (31%) of the control group (adjusted risk ratio [aRR] 0.95, 95% confidence interval [CI] 0.86 to 1.04).
- Similarly, lactoferrin did not affect mortality. There were 71/1,076 (7%) deaths in the lactoferrin group compared with 68/1,076 (6%) in the control group (aRR 1.05, 95% CI 0.66 to 1.68).
- There was no difference in necrotising enterocolitis (a serious bowel disorder), which affected 63/1,085 (6%) of the lactoferrin group compared to 56/1,084 (5%) of the control group (aRR 1.13, 95% CI 0.68 to 1.89).
- There were 16 (1.5%) serious adverse events in the lactoferrin group, two of which may have been related to the trial intervention. Ten (0.9%) adverse events were observed in the control group.
What does current guidance say on this issue?
There are no specific guidelines regarding the use of lactoferrin for the prevention of infection in premature babies. Great Ormond Street Hospital does produce a guideline on enteral feeding in general. This highlights the fact that the incidence of infections in premature neonates receiving human milk is lower due to anti-infective agents including prebiotics, probiotics, immunoglobulins and lactoferrin.
What are the implications?
When lactoferrin was given to babies born before 32 weeks, their risk of acquiring infections, such as sepsis, was virtually the same as those in the control group, about 30%.
This study of more than double the total number of infants from previous trials shows that the addition of lactoferrin to premature infants’ feeds is unnecessary. The threat of late-onset infection remains.
As well as further research into anti-infective agents we must remain focused on what we know works, such as hand hygiene and other infection control procedures.
Citation and Funding
ELFIN trial investigators group. Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. Lancet. 2019;393(10170):423-33.
This project was funded by the NIHR Technology Assessment Programme (10/57/49).
Doyle L, Cheong J. Does bovine lactoferrin prevent late-onset neonatal sepsis? Lancet. 2019; 393(10170):382-84.
Griffiths J, Jenkins P, Vargova M et al. Enteral lactoferrin to prevent infection for very preterm infants: the ELFIN RCT. Health Technol Assess. 2018;22(74).
GOSH. Nutrition: enteral nutrition for the preterm infant. London: Great Ormond Street Hospital; 2016.
Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2017;6:CD007137.
Martin A, Ghadge A, Manzoni P et al; LIFT Collaborative Study Group. Protocol for the Lactoferrin Infant Feeding Trial (LIFT): a randomised trial of adding lactoferrin to the feeds of very-low birthweight babies prior to hospital discharge. BMJ Open. 2018;8(10):e023044.
Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre